Chronic Stress and the Brain–Kidney Axis in Renal Injury: From Neuroendocrine Dysregulation to Kidney Damage
- 1Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Abstract
Chronic stress is a pervasive psychophysiological burden and an independent risk factor for chronic kidney disease (CKD). Large-scale cohort studies confirm that stress exposure significantly increases CKD risk and accelerates renal decline, even after adjusting for traditional confounders. However, the neuroendocrine mechanisms translating stress into direct kidney damage remain unclear. This review focuses on the brain–kidney axis, a bidirectional framework integrating neural, endocrine, and immune signals. Under chronic stress, sustained overactivation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system (SNS), coupled with secondary renin–angiotensin–aldosterone system (RAAS) dysregulation, creates a deleterious intrarenal milieu. Unlike classical models driven by high salt or metabolic disorders, a proposed hallmark of stress-induced injury is the non-classical activation of the mineralocorticoid receptor (MR). Given MR’s equal affinity for cortisol and aldosterone, the protective barrier maintained by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is compromised under persistent glucocorticoid elevation. This may allow cortisol to escape inactivation and aberrantly activate intrarenal MR, a process putatively termed gluco-mineralo cross-activation. This mechanism is hypothesized to initiate profibrotic cascades via NADPH oxidase 4 (NOX4)/ROS/TGF-β/Smad pathways and amplifies the complement C5a-C5a receptor 1 inflammatory axis, culminating in fibrosis and sclerosis. Based on these insights, we propose stress-related kidney disease (SRKD) as a distinct clinical entity. This review synthesizes current evidence to guide precision interventions targeting the brain–kidney axis.
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BibTeX
@article{zhang2026chronic,
title = {{Chronic Stress and the Brain–Kidney Axis in Renal Injury: From Neuroendocrine Dysregulation to Kidney Damage}},
author = {Chunyun Zhang and Cheng Wan and Jing Sun and Zhiwen Wang and Qian Yuan and Chun Zhang},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188356},
url = {https://www.mdpi.com/1422-0067/27/18/8356},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Chronic Stress and the Brain–Kidney Axis in Renal Injury: From Neuroendocrine Dysregulation to Kidney Damage
AU - Chunyun Zhang
AU - Cheng Wan
AU - Jing Sun
AU - Zhiwen Wang
AU - Qian Yuan
AU - Chun Zhang
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188356
UR - https://www.mdpi.com/1422-0067/27/18/8356
AB - Chronic stress is a pervasive psychophysiological burden and an independent risk factor for chronic kidney disease (CKD). Large-scale cohort studies confirm that stress exposure significantly increases CKD risk and accelerates renal decline, even after adjusting for traditional confounders. However, the neuroendocrine mechanisms translating stress into direct kidney damage remain unclear. This review focuses on the brain–kidney axis, a bidirectional framework integrating neural, endocrine, and immune signals. Under chronic stress, sustained overactivation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system (SNS), coupled with secondary renin–angiotensin–aldosterone system (RAAS) dysregulation, creates a deleterious intrarenal milieu. Unlike classical models driven by high salt or metabolic disorders, a proposed hallmark of stress-induced injury is the non-classical activation of the mineralocorticoid receptor (MR). Given MR’s equal affinity for cortisol and aldosterone, the protective barrier maintained by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is compromised under persistent glucocorticoid elevation. This may allow cortisol to escape inactivation and aberrantly activate intrarenal MR, a process putatively termed gluco-mineralo cross-activation. This mechanism is hypothesized to initiate profibrotic cascades via NADPH oxidase 4 (NOX4)/ROS/TGF-β/Smad pathways and amplifies the complement C5a-C5a receptor 1 inflammatory axis, culminating in fibrosis and sclerosis. Based on these insights, we propose stress-related kidney disease (SRKD) as a distinct clinical entity. This review synthesizes current evidence to guide precision interventions targeting the brain–kidney axis.
SN - 1422-0067
ER -